Mammalian bones serve two different and at times incompatible functions. Bones must be strong, light, and be capable of repair and remodeling in response to changing stress. Bones also serve as a metabolic reservoir for most of the calcium and phosphorous in the body, along with substantial amounts of magnesium, sodium, and carbonate.
Bone is a highly specialized connective tissue with unique properties derived from its extensive matrix structure. A network of fibrous bundles composed of the protein collagen is presumed to provide the tension-resistant behavior of bone. In addition, other material including proteoglycans, noncollagenous proteins, lipids, and acidic proteins associated with a mineral compound consisting primarily of hydroxyapatite, Ca.sub.10 (PO.sub.4).sub.6 (OH).sub.2 , are deposited in the extensive matrix architecture of bone. Bone tissue is continuously renewed and remodeled throughout the life of mammals.
The processes of bone formation and renewal are carried out by specialized cells. Osteogenesis is presumably carried out by the "osteoblasts" (bone-forming cells). Remodeling of bone is apparently brought about by an interplay between the activities of bone-resorbing cells called "osteoclasts" and the bone-forming osteoblasts. The bony skeleton is thus not only an architectural structure with a mechanical function but also is a living tissue capable of growth, modeling, remodeling and repair. Since these processes are carried out by specialized living cells, chemical (pharmaceutical/hormonal), physical and physiochemical alterations can affect the quality, quantity, and shaping of bone tissue.
As part of their storage function, bones provide calcium and phosphorous when the supply of these elements is deficient. The sodium, phosphorous, and carbonate are also released to buffer excess acid in the diet. These responses preempt the structural functions of growth and remodeling such that bone mass may decrease due to calcium or phosphorous deficiency or with chronic acidosis.
"Bone demineralization," includes loss of both mineral and protein matrix components, resulting in a reduction in bone mass without a reduction in bone volume. Such demineralization occurs in a wide range of subjects, including post-menopausal women, patients who are undergoing or have undergone long-term administration of corticosteroids, patients suffering from Cushing's syndrome, and in patients having gonadal dysgenesis. Unchecked, the bone demineralization process leads to osteoporosis, a condition characterized by decrease in bone mass (decreased density and enlargement of bone spaces) without a reduction in bone volume producing porosity and fragility. It is estimated that thirty-five percent of women over the age of 65 suffer from osteoporosis. One of the chief rationales for estrogen-replacement therapy in post-menopausal women is avoidance of, or at least slowing down, the bone demineralization process and the onset of osteoporosis. Calcium therapy has been advocated for treatment of osteoporosis, and some steroids related to vitamin D are alleged to reduce the rate of bone resorption. See U.S. Pat. Nos. 4,448,721 and 4,201,881.
The ergoline ring is a tetracycle having the following structure: ##STR2##
Certain substituted ergolines are known to be D-2 dopamine agonists having the ability to inhibit the secretion of prolactin and to affect favorably the symptoms of Parkinson's Syndrome. For example, in the foregoing structure when R is n-propyl, R.sup.1 is methylthiomethyl, and R" is H, the substituted ergoline has been given the generic name pergolide, which is disclosed in U.S. Pat. No. 4,166,182. Pergolide has been proven to be effective in the treatment of some symptoms of Parkinsonism, and is being developed as the mesylate salt.
An object of this invention is to provide a novel therapeutic approach to the inhibition of bone demineralization and, by consequence, of osteoporosis, by administering certain ergoline compounds.